Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, 6-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-ht.sub.5, 5-ht.sub.6 and 5-ht.sub.7 with the 5-HT.sub.1 receptor further divided into the 5-HT.sub.1 A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT.sub.1A autoreceptors are located on the cell bodies in the raphe nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reduce the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the 5-HT.sub.1D receptors (in rodents the 5-HT.sub.1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses, as has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal 5-HT.sub.1D autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. The antagonist would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of 5-HT.sub.1D receptor subtype also exist. A large part of these receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the 5-HT.sub.1D receptor mediates inhibitory responses, an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT. Compounds having 5-HT.sub.1D activity may according to well known and recognized pharmacological tests be divided into full agonists, partial agonists and antagonists.